Remedies or preventives for digestive diseases containing diaminotrifluoromethylpyridine derivatives

ABSTRACT

A digestive system disease therapeutic or preventive agent containing as an active ingredient a diaminotrifluoromethylpyridine derivative represented by the formula (I) or its salt:                    
     wherein X is a —CW 1 R 1  group, a —COCOR 2  group, a —CW 1 NHCOR 2  group, a —C(═W 1 )W 2 R 3  group or a —CW 1 N(R 4 )R 5  group; Y is an alkyl group, a —CW 3 R 6  group, a —COCOR 7  group, a —NHCOR 7  group, a —C(═W 3 )W 4 R 8  group, a —(NH) m SO 2 R 9  group, a —(NH) m SO 2 OR 10  group or a —(NH) m SO 2 N(R 11 )R 12  group; each of R 1 , R 6  and R 9  is a chain hydrocarbon group, a monocyclic hydrocarbon group, a polycyclic hydrocarbon group, a monocyclic heterocycle group or a polycyclic heterocycle group; each of R 2  and R 7  is an-alkyl group, an alkoxy group, a phenyl group or a phenoxy group; each of R 3 , R 8  and R 10  is an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a phenyl group or a benzyl group; each of R 4 , R 5 , R 11  and R 12  is an alkyl group; each of W 1 , W 2 , W 3  and W 4  is an oxygen atom or a sulfur atom; and m is 0 or 1.

TECHNICAL FIELD

The present invention relates to a therapeutic or preventive agentcontaining as an active ingredient a diaminotrifluoromethylpyridinederivative or its salt, useful for digestive system diseases such asinflammatory bowel diseases, gastritis and peptic ulcer.

BACKGROUND ART

Japanese Patent No. 2762323 and U.S. Pat. No. 5,229,403 disclose that adiaminotrifluoromethylpyridine derivative or its salt has aphospholipase A₂ inhibitory action and is useful as an active ingredientof an anti-inflammatory agent or an anti-pancreatitis agent. They alsodisclose that (1) phospholipase A₂ is secreted or activated in platletsor inflammatory cells by stimulations and contributes to the productionof a platlet activating factor (PAF) and arachidonic acid metabolites,(2) the arachidonic acid metabolites are closely related to variousdiseases, for example, inflammatory symptoms such as rheumaticarthritis, arthritis deformans, tendinitis, bursitis, psoriasis andrelated dermatitis; nasal and bronchial airway troubles such as allergicrhinitis and allergic bronchial asthma; and immediate hypersensitivereactions such as allergic conjunctivitis, (3) on the other hand,phospholipase A₂ secreted from pancreas is activated in the intestineand exhibits a digestive action, but once activated in the pancreas, itis believed to be one of the factors causing pancreatitis, and (4) theabove diaminotrifluoromethylpyridine derivative inhibits phospholipaseA₂ and thus is effective for treatment of diseases related tophospholipase A₂ such as inflammatory symptoms, nasal and bronchialairway troubles, immediate hypersensitive reactions or pancreatitis, andcan be used as an anti-inflammatory agent, an agent for treatingbronchial asthma, an anti-allergy agent, an anti-pancreatitis agent, ananti-nephritis agent or an anti-multiple organ failure agent.

Further, U.S. Pat. No. 5,492,908 discloses that such compounds can beused as a therapeutic agent for rheumatoid arthritis, and JP-A-10-298076discloses that some of these compounds are effective as an anticanceragent having a carcinogenesis inhibitory effect.

Among digestive system diseases, diseases for which new therapeuticagents are particularly required, may, for example, be inflammatorybowel diseases, gastritis and peptic ulcer. The inflammatory boweldiseases are meant for enteritis developed at small intestine (includingduodenum, jejunum and ileum) or large intestine (including cecum, colonand rectum), and they include enteritis, the causes of which are clear,such as infectious enteritis, ischemic enteritis, radioenteritis, drugenteritis and irritable bowel syndrome, intractable inflammatory boweldiseases, the causes of crises of which have not been clear yet, such asulcerative colitis (nonspecific idiopathic colitis), Crohn's disease(regional enteritis), Crohn's disease of large bowel (granulomatouscolitis or regional colitis) and entero-Behcet's disease, and furtherinclude enteritis, not only the causes of which have not been understoodyet but also which themselves have not been specified.

Human ulcerative colitis is nonspecific idiopathic inflammatory boweldisease which forms erosion or ulcer on lamina propria mucosa orsubmucosa of large intestine mucosa from rectum to cecum, and it hasconventionally been a relatively rare disease, however, the number ofpatients are rapidly increasing in recent years. As its clinicalsymptoms, characteristic pathognomonic findings such as diarrhea, bloodystool, abdominal pain and weight reduction may be mentioned, and it isan intractable disease with repetition of recurrence and remission. Itsdetailed cause and morbidity have not been clearly understood yet, butimmunopathological mechanism and psychological factor are considered tobe related. On the other hand, Crohn's disease is a disease whereininflammation is formed not only on the mucosa but on entire bowel walland non-diffusive and discontinuous lesion is formed on the entiredigestive canal from the mouth cavity to the anus, and its detailedcause of disease has not been understood yet. During progress of thedisease, in addition to denutrition, various serious digestive organ andparenteral symptoms such as intestinal stenosis, intestinal perforation,abdominal abscess and massive bleeding are likely to coincide, and therecurrence rate after operations is high with this disease.

As medical treatment for the ulcerative colitis, steroid hormone,Salazosulfapyridine (SASP) [Salazopyrin®, registered trademark] andmetronidazole [Flagyl®, registered trademark] are mainly used [NewEngland Journal of Medicine, vol. 25, p.1499 (1980), The Merck Manual,Seventeenth Edition, p.309, (1999)]. SASP used as the first choice drugparticularly for active ulcerative colitis at a minor to moderate stage,which is an azo compound of 5-aminosalicylic acid (5-ASA) andsulfapyridine, is effective only when lesion is present in the largeintestine, its effect is relatively weak at a severe stage, and it is inmany cases used together with another agent such as a steroid drug evenat a minor stage. Further, it is also pointed out that the effect isinsufficient at an acute stage of inflammation. Its detailed mechanismof action is still unclear in many points even though its variousactions have been reported such as prostaglandin synthesis inhibitoryaction, leukotriene synthesis inhibitory action, leukocyte chemotaxisinhibitory action, oxygen radical production inhibitory and erasingaction, immunosuppressive action and anti-inflammatory action. Further,by taking the drug, adverse reactions such as liver function failure,nausea and vomiting, headache, pyrexia, hemolytic anemia, malesterility, abdominal dysphoria, rash, lymph node swelling,granulocytopenia and folic acid deficiency appear, and the frequencyreaches 10 to 20% [Gastrointestinal Pharmacology, vol.21, p.643-658(1992)]. With a purpose of decreasing such adverse reactions, mesalazinewhich is a sustained release preparation coated so that 5-ASA is formedby the pH in the intestine has been developed and used clinically, butthe same problems as in the case of the above-described SASP have beenreported, and its effect does not exceed SASP [Japanese Pharmacology &Therapeutics, vol.22, p.93-121 (1994)]. On the other hand,adrenocorticosteroids such as Predonine or Rinderon have commonly beenused, however, on the other side of the therapeutic effect, otheradverse reactions due to virus and bacterial infection or suppression ofpituitary gland and adrenal cortex function have been pointed out asproblems [Sogo Rinsho (Comprehensive Clinic), vol.43, p.1725-1729(1994)], and because the prescription is very difficult, carefuladministration under hospitalization control is basically required. Astherapeutic agents effective for Crohn's disease, SASP, 5-ASA,mercaptopurine, adrenocorticosteroid and metronidazole may, for example,be mentioned, but none of them is considered to have a sufficientclinical effect.

In recent years, for such inflammatory bowel diseases, new therapeuticagents such as a lipoxygenase inhibitor, a thromboxane A₂ receptorantagonist, a thromboxane A₂ synthetase inhibitor, an oxygen radicalremoving agent, an interleukin 1 (IL-1) antagonist (JP-A-9-157182) and aneutralizing antibody against tumor necrosis factor (TNF-α), andleukocytapheresis have been developed, however, development of moreeffective and safer therapeutic agents has been desired.

On the other hand, digestive ulcer such as gastric ulcer or duodenalulcer exhibits various symptoms depending upon the location of the ulcerand the age of the patient, and the main cause has classically beenconsidered as hypersecretion of gastric acid. As gastric acidhypersecretion inhibitors, H₂ blockers having a H₂ receptor antagonisticaction (such as cimetidine, ranitidine, famotidine, roxatidine acetateand nizatidine) and proton pump inhibitors (PPI: such as omeprazole andlansoprazole) have been used clinically. No one disputes that the curerate of gastric ulcer and duodenal ulcer was remarkably improved byappearance of these drugs, and these drugs are mainly used for thetreatment against digestive ulcer at present. However, many clinicalcases have been reported that even though the ulcer is temporarily curedby such a drug, the ulcer recrudesces with a high ratio so long asHelicobacter pylori is present in the digestive canal [New EnglandJournal of Medicine, vol.328, p.308 (1993)] as described hereinafter.Further, the incidence of digestive ulcer due to application of anonsteroidal anti-inflammatory agent tends to be high with patients whotake an H₂ blocker or PPI for a long period of time, such beingproblematic.

In recent years, it has been clarified that Helicobacter pylori is animportant pathogenic factor in crisis of gastritis, gastric ulcer,duodenal ulcer and stomach cancer [American Journal of Gastroenterology,vol.82, p.2283 (1987)], and a treatment with an antibacterial agent inaddition to a gastric acid secretion inhibitor has been applied toHelicobacter pylori positive digestive ulcer cases regardless of whetherit is initial crisis or recurrent crisis. There are various opinionswith regard to the action of Helicobacter pylori, and according to onetheory, it has been reported that urease produced by Helicobacter pyloriunder an acidic condition decomposes urea present in the stomach toproduce ammonia, and the produced ammonia directly impairs the gastricmucosa [Journal of Dairy Science, vol.67, p.481 (1984)]. As bacterialelimination treatment against Helicobacter pylori, various treatmentmethods employing mainly a bismuth preparation, an antibacterial agentor an antiprotozoan agent have been devised, however, no sufficientbacterial elimination effect can be obtained by single use of thesedrugs, and the treatment is carried out mainly by multiple drugcombination. For example, in Europe and U.S., classical three-drugcombination treatment with bismuth, metronidazole and tetracycline hasbeen carried out, and a bacterial elimination ratio of at least 90% canbe obtained, however, appearance of adverse reactions with highfrequency and complicated method of application lead to poor compliance,and such a treatment is not widely used in Japan. Further, two drugcombination treatment by PPI and an antibacterial agent such asamoxicillin or clarithromycin, or a short-term three drug combinationtreatment wherein omeprazole, clarithromycin and nitroimidazole in usualdosage are used together for one weak, have been developed. However,many cases where no stable bacterial elimination ratio can be obtainedor cases where recurrence takes place due to appearance of resistantbacterium, have been reported. Further, as application of anantibacterial agent in a large amount is required, it is hard forpatients to take the agent, and it is known that adverse reactions suchas diarrhea, nausea and vomiting occur in many cases, and such isgenerally known as a problem to be overcome.

Gastritis caused by impairment of the gastric mucosa are roughlyclassified into acute erosive gastritis, chronic erosive gastritis andnonerosive gastritis, postgastrectomy gastritis and other gastritissyndrome. The causes are various but many of them are in common with thecases of the above-described digestive ulcer, and the mainstream of thetreatment method at present is single or combination use of H₂ blockers,proton pump inhibitors and Helicobacter pylori elimination agents. Fromrecent studies, it has been reported that as novel therapeutic agentsfor digestive ulcer or gastritis, a digestive canal mucosa adherentanti-helicobacter pylori agent containing an antibacterial substance andan antiulcer substance (JP-A-7-126189, JP-A-10-167985), acholecystokinin antagonist (JP-A-8-259447), a mucin productionaccelerator containing lactoferrin as an active ingredient(JP-A-9-12473), an aminoalkylpyridyloxy derivative having both H₂receptor antagonistic action and gastric mucosa protective action(JP-A-11-92373), etc., are useful.

Further, JP-A-11-12171, JP-A-10-330346 and JP-A-10-101576 disclose thata 1,4-benzodioxin derivative having a selective β₃ receptor agonisticaction, a straight chain nitron derivative having a free radicalscavenging action and a drug containing Gricetin and glutamine (or aglutamine derivative) as active ingredients, respectively, are usefulfor treatment of various digestive system diseases, however, developmentof safer drugs having more excellent therapeutic effects has beendesired.

DISCLOSURE OF THE INVENTION

The present inventors have conducted extensive studies onpharmacological effects of diaminotrifluoromethylpyridine derivatives ortheir salts and as a result, found that these compounds have excellenttherapeutic effects on digestive system diseases such as inflammatorybowel disease, gastritis and peptic ulcer, and the present invention hasbeen accomplished on the basis of this discovery.

The present invention provides a therapeutic or preventive agent fordigestive system diseases, containing as an active ingredient adiaminotrifluoromethylpyridine derivative represented by the formula (I)or its salt:

wherein X is a —CW¹R¹ group, a —COCOR² group, a —CW¹NHCOR² group, a—C(═W¹)W²R³ group or a —CW¹N(R⁴)R⁵ group; Y is an alkyl group, a —CW³R⁶group, a —COCOR⁷ group, a —NHCOR⁷ group, a —C(═W³)W⁴R⁸ group, a—(NH)_(m)SO₂R⁹ group, a —(NH)_(m)SO₂OR¹⁰ group or a—(NH)_(m)SO₂N(R¹¹)R¹² group; each of R¹, R⁶ and R⁹ which are independentof one another, is a chain hydrocarbon group which may be substituted, amonocyclic hydrocarbon group which may be substituted, a polycyclichydrocarbon group which may be substituted, a monocyclic heterocyclegroup which may be substituted or a polycyclic heterocycle group whichmay be substituted; each of R² and R⁷ which are independent of eachother, is an alkyl group which may be substituted, an alkoxy group whichmay be substituted, a phenyl group which may be substituted or a phenoxygroup which may be substituted; each of R³, R⁸ and R¹⁰ which areindependent of one another, is an alkyl group which may be substituted,an alkenyl group which may be substituted, an alkynyl group which may besubstituted, a cycloalkyl group which may be substituted, a phenyl groupwhich may be substituted or a benzyl group which may be substituted;each of R⁴, R⁵, R¹¹ and R¹² which are independent of one another, is analkyl group which may be substituted; each of W¹, W², W³ and W⁴ whichare independent of one another, is an oxygen atom or a sulfur atom; andm is 0 or 1, excluding a case where one of X and Y is a —COCF₂X¹ group(wherein X¹ is a hydrogen atom, a halogen atom, an alkyl group or ahaloalkyl group), and the other is a —COCF₂X² group (wherein X² is ahydrogen atom, a halogen atom, an alkyl group, a haloalkyl group or analkylcarbonyl group), a —COOX³ group (wherein X³ is an alkyl group whichmay be substituted or a phenyl group which may be substituted) or a—COX⁴ group (wherein X⁴ is an alkyl group, a haloalkyl group, an alkenylgroup, an alkynyl group, a phenyl group which may be substituted, afuranyl group or a naphthyl group).

In the above formula (I), the above chain hydrocarbon group for each ofR¹, R⁶ and R⁹ may, for example, be an alkyl group, an alkenyl group oran alkynyl group. The above monocyclic hydrocarbon group may be acycloalkyl group, a cycloalkenyl group or a phenyl group. The polycyclichydrocarbon group may, for example, be a condensed polycyclichydrocarbon group such as a naphthyl group, a tetrahydronaphthyl groupor an indanyl group, or a bridged polycyclic hydrocarbon group such asan adamantyl group, a noradamantyl group, a norbornanyl group or anorbornanonyl group, and the above monocyclic heterocycle group may, forexample, be a pyrrolyl group, a furanyl group, a thienyl group, apyrazolyl group, an imidazolyl group, an oxazolyl group, an isoxazolylgroup, a thiazolyl group, an isothiazolyl group, a thiadiazolyl group, apyrrolinyl group, a pyrrolidinyl group, a dihydrofuranyl group, atetrahydrofuranyl group, a dihydrothienyl group, a tetrahydrothienylgroup, a pyrazolinyl group, a hydantoinyl group, an oxazolinyl group, anisoxazolinyl group, an isoxazolidinyl group, a thiazolinyl group, athiazolidinyl group, a dioxolanyl group, a dithiolanyl group, a pyridylgroup, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, adihydropyridyl group, a tetrahydropyridyl group, a piperidinyl group, adihydrooxopyridazinyl group, a tetrahydrooxopyridazinyl group, adihydrooxopyrimidinyl group, a tetrahydrooxopyrimidinyl group, apiperazinyl group, a dihydropyranyl group, a tetrahydropyranyl group, adioxanyl group, a dihydrodithinyl group, a dithianyl group or amorphorinyl group. The above polycyclic heterocycle group may be acondensed polycyclic heterocycle group such as a thienothienyl group, adihydrocyclopentathienyl group, an indolyl group, a benzofuranyl group,a benzothienyl group, a benzoxazolyl group, a benzisoxazolyl group, abenzothiazolyl group, a benzimidazolyl group, a tetrahydrobenzothienylgroup, a dihydrobenzofuranyl group, a tetrahydrobenzisoxazolyl group, abenzodioxolyl group, a quinolinyl group, an isoquinolinyl group, abenzodioxanyl group or a quinoxalinyl group, or a bridged polycyclicheterocycle group such as a quinuclidinyl group.

The substituent for each of the chain hydrocarbon group which may besubstituted for each of R¹, R⁶ and R⁹, the alkyl group which may besubstituted and the alkoxy group which may be substituted for each of R²and R⁷, the alkyl group which may be substituted, the alkenyl groupwhich may be substituted and the alkynyl group which may be substitutedfor each of R³, R⁸ and R¹⁰, the alkyl group which may be substituted foreach of R⁴, R⁵, R¹¹ and R¹², and the alkyl group which may besubstituted for X³, may, for example, be a halogen atom, an alkoxygroup, a haloalkoxy group, an alkylthio group, a cycloalkyl group, acycloalkoxy group, a cycloalkenyl group, a cycloalkenyloxy group, analkoxycarbonyl group, an alkylcarbonyl group, an alkylcarbonyloxy group,an aryl group, an aryloxy group, an arylthio group, an amino group or anamino group substituted with an alkyl group. The number of suchsubstituents or substituents on such substituents may be one or more,and when the number is two or more, such substituents may be the same ordifferent.

Further, the substituent for each of the monocyclic hydrocarbon groupwhich may be substituted, the polycyclic hydrocarbon group which may besubstituted, the monocyclic heterocycle group which may be substitutedand the polycyclic heterocycle group which may be substituted for eachof R¹, R⁶ and R⁹, the phenyl group which may be substituted and thephenoxy group which may be substituted for each of R² and R⁷, thecycloalkyl group which may be substituted, the phenyl group which may besubstituted and the benzyl group which may be substituted for each ofR³, R⁸ and R¹⁰, and the phenyl group which may be substituted for X³,may, for example, be a halogen atom, an alkyl group, a haloalkyl group,an alkoxy group, a haloalkoxy group, an alkylthio group, a cycloalkylgroup, a cycloalkoxy group, a cycloalkenyl group, a cycloalkenyloxygroup, an alkoxycarbonyl group, an alkylcarbonyl group, analkylcarbonyloxy group, an aryl group, an aryloxy group, an arylthiogroup, an amino group, an amino group substituted with an alkyl group, acyano group or a nitro group. The number of such substituents orsubstituents on such substituents may be one or more, and when thenumber is two or more, such substituents may be the same or different.

In the formula (I), the alkyl group and the alkyl moiety contained ineach of X and Y may, for example, be C₁₋₁₈ alkyl such as a methyl group,an ethyl group, a propyl group, a butyl group, a pentyl group, a hexylgroup, a heptyl group, an octyl group, a decyl group or a nonadecylgroup, and they include linear or branched aliphatic structural isomers.The alkenyl group and the alkenyl moiety contained in each of X and Ymay be C₂₋₁₈ alkenyl such as a vinyl group, a propenyl group, a butenylgroup, a pentenyl group, a hexenyl group, a decenyl group or anonadecenyl group, and they include linear or branched aliphaticstructural isomers. The alkynyl group and the alkynyl moiety containedin each of X and Y may be C₂₋₁₈ alkynyl such as an ethynyl group, apropynyl group, a butynyl group, a pentynyl group, a hexynyl group, adecynyl group or a nonadecynyl group, and they include linear orbranched aliphatic structural isomers. The cycloalkyl group and thecycloalkyl moiety contained in each of X and Y may be C₃₋₈ cycloalkylsuch as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, acyclohexyl group or a cyclooctyl group. The cycloalkenyl group and thecycloalkenylmoiety contained in each of X and Y may be C₅₋₈ cycloalkenylsuch as a cyclopentenyl group, a cyclohexenyl group or a cyclooctenylgroup. Further, the halogen atom contained in each of X and Y may be afluorine atom, a chlorine atom, a bromine atom or an iodine atom. Thearyl group and the aryl moiety contained in each of X and Y may, forexample, be a phenyl group, a thienyl group, a furanyl group, a pyridylgroup, a naphthyl group, a benzothienyl group, a benzofuranyl group or aquinolinyl group.

Now, preferred embodiments of the compounds of the present inventionwill be described. In the formula (I), it is preferred that X is a—CW¹R¹ group or a —C(═W¹)W²R³ group and Y is a —SO₂R⁹ group. Each of R¹and R⁶ is preferably an alkyl group which may be substituted, an alkenylgroup which may be substituted, a cycloalkyl group which may besubstituted, a cycloalkenyl group which may be substituted, a phenylgroup which may be substituted, a tetrahydronaphthyl group which may besubstituted, an indanyl group which may be substituted, a furanyl groupwhich may be substituted or a thienyl group which may be substituted;more preferably an alkyl group, a haloalkyl group, analkoxycarbonylalkyl group, an alkenyl group, a haloalkenyl group, acycloalkyl group, a cycloalkyl group substituted with a halogen atom, aphenyl group, a phenyl group substituted with a halogen atom, a phenylgroup substituted with an alkyl group or a haloalkyl group, a phenylgroup substituted with an alkoxy group or a haloalkoxy group, atetrahydronaphthyl group, an indanyl group, a furanyl group or a thienylgroup. Each of R² and R⁷ is preferably an alkoxy group which may besubstituted or a phenyl group which may be substituted; more preferablyan alkoxy group, a haloalkoxy group, a phenyl group or a phenyl groupsubstituted with a halogen atom. Each of R³, R⁸ and R¹⁰ is preferably analkyl group which may be substituted; more preferably an alkyl group ora haloalkyl group. Each of R⁴, R⁵, R¹¹ and R¹² is preferably an alkylgroup. R⁹ is preferably an alkyl group which may be substituted, analkenyl group which may be substituted, a cycloalkyl group which may besubstituted, a cycloalkenyl group which may be substituted or a phenylgroup which may be substituted; more preferably an alkyl group, ahaloalkyl group, a phenyl group, a phenyl group substituted with ahalogen atom, a phenyl group substituted with an alkyl group or ahaloalkyl group or a phenyl group substituted with an alkoxy group or ahaloalkoxy group.

Preferred compounds among the compounds of the present invention arecompounds of the above formula (I) wherein X is analkoxycarbonylalkylcarbonyl group, an alkenylcarbonyl group, analkenylcarbonyl group substituted with a thienyl group, acycloalkylcarbonyl group, an indanylcarbonyl group, a furancarbonylgroup, a thiophenecarbonyl group, a tetrahydronaphthylcarbonyl group ora benzoyl group which may be substituted with a halogen atom or ahaloalkyl group, and Y is an alkylsulfonyl group. Specific compoundsincludeN-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)-4-fluorobenzamide,N-(2-isopropylsulfonylamino-5-trifluoromethyl-3-pyridyl)-3-fluorobenzamide,N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)-2-furancarboxamide,N-(2-isopropylsulfonylamino-5-trifluoromethyl-3-pyridyl)cyclopentanecarboxamide,N-(2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl)cyclohexanecarboxamide,N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)-5-indanecarboxamide,N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)acetoxyacetamide,N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)crotonamide,N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)-2-thiophenecarboxamide,N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)-3-trifluoromethylbenzamide,N-(2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl)-3-fluorobenzamide,N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)-6-(1,2,3,4-tetrahydronaphthalene)carboxamide,N-(2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl)crotonamide,N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)-3-(2-thienyl)acrylamide,and their salts.

More preferred compounds may be compounds of the above formula (I)wherein X is a cycloalkylcarbonyl group, a furancarbonyl group or abenzoyl group which may be substituted with halogen, and Y is analkylsulfonyl group. Specific compounds includeN-(2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl)cyclohexanecarboxamide,N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)-4-fluorobenzamide,N-(2-isopropylsulfonylamino-5-trifluoromethyl-3-pyridyl)-3-fluorobenzamide,N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)-2-furancarboxamideandN-(2-isopropylsulfonylamino-5-trifluoromethyl-3-pyridyl)cyclopentanecarboxamide,and their salts.

The compounds represented by the formula (I) may form a salt when Y is—SO₂R⁹ group (wherein R⁹ is as defined above). Such a salt may be anypharmaceutically acceptable salt, for example, an alkali metal salt suchas a potassium salt or a sodium salt, an alkaline earth metal salt suchas a calcium salt, or an organic amine salt such as a triethanolaminesalt or a tris(hydroxymethyl)aminomethane salt. Such a salt may havecrystal water.

The compounds represented by the formula (I) can be prepared, forexample, by a process as disclosed in Japanese Patent No. 2762323.Further, these compounds have geometrical isomers depending upon thetype of their substituents, and the present invention include isomers(cis-forms and trans-forms) and isomer mixtures.

The compounds of the present invention represented by the above formula(I) are useful as an active ingredient for a therapeutic or preventiveagent for digestive system diseases. Particularly, they are useful as anactive ingredient for a therapeutic or preventive agent for inflammatorybowel diseases such as ulcerative colitis (nonspecific idiopathiccolitis), Crohn's disease (regional enteritis), large intestine Crohn'sdisease (granulomatous colitis or regional colitis), entero-Behcet'sdisease, infectious enteritis, ischemic enteritis, radioenteritis, drugenteritis and irritable bowel syndrome, digestive ulcer such as gastriculcer and duodenal ulcer, and gastritis. They are particularly useful asan active ingredient for a therapeutic or preventive agent for the aboveulcerative colitis, Crohn's disease, large intestine Crohn's disease andentero-Behcet's disease, and they are preferably used as an activeingredient for a therapeutic or preventive agent for ulcerative colitisand Crohn's disease. Further, they are expected to be more effective bycombination with another drug such as Chinese herbal remedy.

To administer the compound of the present invention as an activeingredient for a therapeutic drug for digestive system diseases such asulcerative colitis, Crohn's disease, gastric ulcer, duodenal ulcer andgastritis, it is formulated alone or together with a pharmaceuticallyacceptable carrier into a drug composition suitable for peroral orparenteral administration, such as a tablet, a powder, a capsule, agranule, an injection drug, an ointment, an inhalant, an enema or asuppository, and it is administered in the form of such a drugformulation. Further, in recent years, a drug formulation comprising asuppository base and a digestive canal mucosa adhesive matrix forperoral administration incorporated into the base, the matrix beingcapable of prolonging the retention time in the digestive canal to makethe active ingredient for a drug for gastric, duodenal, large intestine,small intestine or rectal ulcer affect over a long period of time at ahigh concentration with a high efficiency, utilizing adhesive propertyto the gastric mucosa or intestinal canal mucosa, has been reported(JP-A-5-132416, JP-A-7-330582), and administration employing it is alsopossible.

As a drug formulation suitable for peroral administration, a solidcomposition such as a tablet, a capsule, a powder, a granule or atroach; or a liquid composition such as a syrup suspension, may, forexample, be mentioned. The solid composition such as a tablet, acapsule, a powder, a granule or a troach may contain a binder such asfine crystalline cellulose, gum arabic, tragacanth gum, gelatine orpolyvinyl pyrrolidone; an excipient such as starch, lactose orcarboxymethyl cellulose; a disintegrator such as arginic acid, cornstarch or carboxymethyl cellulose; a lubricant such as magnesiumstearate, light silicic anhydride or colloidal silicon dioxide; asweetener such as sucrose; or a flavoring agent such as peppermint ormethyl salicylate. The liquid composition such as a syrup or asuspension may contain sorbitol, gelatine, methyl cellulose,carboxymethyl cellulose, a vegetable oil such as a peanut oil, anemulsifier such as lecithin as well as a sweetener, a preservative, acolorant or a flavoring agent, as the case requires. Such a compositionmay be provided in the form of a dried formulation. These formulationspreferably contain from 1 to 95 wt % of the active ingredient compound.

A drug formulation suitable for parenteral administration may, forexample, be an injection drug. The injection drug may be prepared bydissolving the compound in the form of a salt in usual water forinjection, or may be formulated into a formulation suitable forinjection such as a suspension or an emulsion (in a mixture with amedically acceptable oil or liquid). In such a case, it may containbenzyl alcohol as an antibacterial agent, ascorbic acid as anantioxidant, a medically acceptable buffer solution or a reagent foradjusting the osmotic pressure. Such an injection drug preferablycontains from 0.1 to 8 wt % of the active ingredient compound.

A drug formulation suitable for topical or per rectal administrationmay, for example, be an inhalant, an ointment, an enema or asuppository. The inhalant may be formulated by dissolving the compoundof the present invention alone or together with a medically acceptableinert carrier in an aerosol or nebulizer solution, or may beadministered to the respiratory airway in the form of fine powder forinhalation. In the case of fine powder for inhalation, the particle sizeis usually not more than 50μ, preferably not more than 10μ. Such aninhalant may be used, if necessary, in combination with otherantiasthematic agent or bronchodilator.

An ointment may be prepared by a conventional method by an addition ofe.g. a commonly employed base. The ointment preferably contains from 0.1to 30 wt % of the active ingredient compound.

The suppository may contain a carrier for formulation which is wellknown in this field, such as polyethylene glycol, lanolin, cacao butteror fatty acid triglyceride. The suppository preferably contains from 0.1to 95 wt % of the active ingredient compound.

The above drug compositions suitable for peroral, parenteral, topical orper rectal administration, may be formulated by known methods so thatafter administration to a patient, the active ingredient will be rapidlydischarged, gradually discharged or belatedly discharged.

Needless to say, the dose of the compound of the present inventionvaries depending upon the type of the compound, the administrationmethod, the condition of the patient or the animal to be treated, andthe optimum dose and the number of administration under a specificcondition must be determined by the judgment of a competent doctor.Usually, however, a daily dose to an adult is from about 0.1 mg to about10 g, preferably from about 1 mg to about 1 g. In the case of the aboveinhalation method, the dose of the compound of the present invention ispreferably from about 0.01 mg to about 1 g per administration.

Now, specific Formulation Examples of the therapeutic or preventiveagent of the present invention will be given. However, the formulationof the present invention is not limited thereto.

FORMULATION EXAMPLE 1 (Tablet)

(1) Active ingredient 20 mg (2) Lactose 150 mg  (3) Starch 30 mg (4)Magnesium stearate  6 mg

The above composition is tabletted so that the components (1) to (4)constitute one tablet.

FORMULATION EXAMPLE 2)Powder, Subtilized Granule or Granule)

(1) Active ingredient 20 mg (2) Sugar ester (DK ester F-160, tradename,180 mg  manufactured by DAI-ICHI KOGYO SEIYAKU CO., LTD.) (3) Surfactant(Dekagreen 1-L, tradename, 15 mg manufactured by Nikko Chemicals Co.,Ltd.) (4) Light silicic anhydride 25 mg

The above components (1) to (4) are mixed and formed into a powder, orsubtilized granule or granule by granulation. Such a powder, subtilizedgranule or granule may be sealed in a capsule to obtain a capsule drug.

FORMULATION EXAMPLE 3 (Hard Gelatine Capsule Drug)

(1) Active ingredient 25 mg (2) Starch 200 mg  (3) Magnesium stearate 10mg

The above components (1) to (3) are packed in one hard gelatine capsuleto obtain a hard gelatine capsule drug.

FORMULATION EXAMPLE 4 (Injection Drug)

(1) Active ingredient  1 mg (2) Glucose 10 mg (3)tris(hydroxymethyl)aminomethane 2.16 mg  

A tris buffer containing the components (1) to (3) is freeze-dried toprepare an injection drug.

FORMULATION EXAMPLE 5 (Ointment for External Skin Application)

(1) Active ingredient 0.5 g (2) White vaseline 25 g (3) Stearyl alcohol22 g (4) Propylene glycol 12 g (5) Sodium lauryl sulfate 1.5 g (6) Ethylparahydroxybenzoate 0.025 g (7) Propyl parahydroxybenzoate 0.015 g (8)Purified water 100 g

The components (1) to (8) are formulated into an ointment for externalskin application by a usual method for preparation of an ointment.

FORMULATION EXAMPLE 6 (Enema Formulation)

(1) Active ingredient 50 mg (2) Macrogol 400 2 g (3) Dipotassiumphosphate 141 mg (4) Potassium dihydrogenphosphate 44 mg (5) Methylparahydroxybenzoate 20 mg (6) Purified water 50 g

The active ingredient and methyl parahydroxybenzoate are added toMacrogol 400, followed by stirring to obtain a mixture, to which oneobtained by adding dipotassium phosphate and potassiumdihydrogenphosphate to the purified water is gradually added to preparean enema formulation.

FORMULATION EXAMPLE 7 (Suppository)

(1) Active ingredient   50 mg (2) Higher fatty acid glyceride 1,650 mg

The component (1) is dispersed or dissolved in (2), and packed andsealed in a plastic container having a size appropriate as asuppository, followed by cooling for solidification to prepare asuppository.

FORMULATION EXAMPLE 8 (Rectum Remaining Suppository, Controlled ReleaseSuppository)

(1) Active ingredient  1 g (2) Witepsol W35 19 g

The component (1) is admixed with preliminarily heated and dissolved(2), and the admixture is packed and sealed in a plastic containerhaving a size appropriate as a suppository, followed by cooling forsolidification to prepare a suppository.

EXAMPLES Test Example 1

As an ulcerative colitis model, trinitrobenzenesulfonic acid (TNB) isusually used, but as a drug effect evaluation system to accomplish thepresent invention, a rat sodium dextran sulfate (DSS) induced ulcerativecolitis model was used. It has been well known that said model isconsidered as an experimental model similar to human ulcerative colitisfrom many viewpoints such as inhibision of weight gain, presence orabsence of bloody stool, symptoms of e.g. anemia and formation oferosion at the large intestine, and no formation of lesion in the smallintestine [FOLIA PHARMACOLOGICA JAPONICA vol. 105, p. 145-152(1995)]. Atherapeutic effect ofN-(2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl)cyclohexanecarboxamidesodium salt monohydrate (hereinafter referred to as compound 1) over thetest system was examined.

The compound 1 was used as a drug formulation. The formulationcomposition (content per one vial) was as follows.

(a) Compound 1 (as anhydride) 100 mg (b) Mannitol (manufactured by KYOWAHAKKO 100 mg KOGYO CO., LTD.) (c) Tris(hydroxymethyl)aminomethane 21.6mg  (manufactured by JUNSEI CHEMICAL) (d) Hydrochloric acid(manufactured by optimum amount SANKYO KAGAKU) (e) Sodium hydroxide(manufactured by optimum amount Nippon Rika) (f) Distilled water  10 mlpH 8.7 ± 0.5

(1) Ulcerative Colitis Induction Method

A 3% aqueous solution of sodium dextran sulfate (DSS: manufactured byWako Pure Chemical Industries, Ltd.) was put in a drinking bottle, andrats [Crj: CD(SD), male, Charles River Japan, 7 weeks old when subjectedto the test] were made to drink the solution freely for 11 days to causecolitis. After eleven days, rats which satisfied selection standards(among rats which discharged bloody stool continuously for at least twodays including the selection day, ones having a weight loss at theselection day of less than 20 g as compared with the weight on theprevious day and having a hemoglobin concentration of at least 12 g/dl)were selected, and divided into groups (ten rats/group) so that therewould be no difference in the average weight among groups.

With respect to a non-treated group and groups treated with the compound1, the 3% aqueous solution was changed to a 1% DSS aqueous solution atthe day of division, and the rats were made to drink the solution freelyfor 14 days. Further, to the rats in the groups treated with thecompound 1, the compound 1 was perorally administered once a day for 14days from the day of division by means of a peroral sonde (dosage: 10ml/kg). To the rats in the non-treated group and a normal group,distilled water for injection (manufactured by Otsuka PharmaceuticalCo., Ltd.) alone was perorally administered similarly. Here, the normalgroup rats were made to drink distilled water for injection freelyinstead of the DSS aqueous solution from initiation of the test to theday of anatomy.

A 10 mg/ml aqueous solution of the compound 1 was prepared by usingdistilled water for injection (manufactured by Otsuka PharmaceuticalCo., Ltd.) and administered to the rats in a desired dosage.

(2) Evaluation Method

Length of Large Intestine and Erosion Area of Large Intestine Mucosa

Immediately after collection of blood, the large intestine (colon andrectum) was excised, and its length was measured by means of a ruler ina sufficiently relaxed state.

Immediately after the measurement, a fixing liquid was injected into theintestine, and the intestine was temporarily fixed for at least 1 hourin such a state that the lumen was approximately uniformly expanded.Then, the intestinal canal was dissected along the mesenterium adheredportion, and the intestine was completely fixed in an expanded state ina 10% neutral buffering formalin aqueous solution for at least one week.The intestine was washed with running water for about 5 minutes, andfurther washed with purified water three times, and then immersed in a3% aqueous acetic acid solution for about 5 minutes as a pretreatment.Then, the intestine was immersed in a 1% Alcian blue (manufactured byNacalai Tesque) (dissolved in a 3% aqueous acetic acid solution) anddyed for about 20 minutes, and then washed with a 3% aqueous acetic acidsolution from 4 to 5 times until elution of Alcian blue disappeared. Bythis operation, the large intestine was dyed in blue with graduation,and the erosion portion was dyed in deep blue, and the area of theportion was analyzed by means of an image analyzer (general purposeimage processing “WinROOF, Version 3.1”, manufactured by MITANICORPORATION) to obtain an erosion area.

The erosion suppression rate of the groups treated with the compound 1was obtained taking the erosion area of the non-treated group as 100.

Erosion suppression rate (%)=[1−(average of erosion area of the groupstreated with the compound 1/average of erosion area of the non-treatedgroup)]×100

Histopathological examination: The large intestine, spleen, mesenteriumand mesenteric lymph node, and femur bone marrow were fixed with a 10%neutral buffering formalin aqueous solution [prepared by using formalin(manufactured by Kishida Chemical Co., Ltd.), disodium hydrogenphosphate (manufactured by Wako Pure Chemical Industries, Ltd.) andsodium dihydrogen phosphate dihydrate (manufactured by Wako PureChemical Industries, Ltd.)], and a histopathological preparation havinghematoxylin-eosin (manufactured by MERCK & CO., INC.) bichrome stainapplied thereto in accordance with a conventional method was preparedand subjected to microscopic examination (by means of BX50, manufacturedby OLYMPUS OPTICAL CO., LTD.).

(3) Results

Erosion area of large intestine: The compound 1 was perorallyadministered once a day over 2 weeks in a dose of 100, 10 or 1mg/kg/day, and as a result, a suppression rate of 62, 56 or 45% in alarge intestine erosion area as compared with the non-treated group wasshown, and remarkable erosion suppression effect was confirmed (Table1). Non erosion in large intestine was confirmed in the normal group.

TABLE 1 Effect on erosion area Dose of Erosion Significant test compound1 suppression rate (non-treated group (mg/kg/day) (%) v.s. treatedgroup) 100 62 P < 0.01 (Williams test) 10 56 P < 0.01 (Williams test) 145 P < 0.05 (Williams test)

Length of large intestine: Further, it was also shown from studies onthe length of the large intestine that the compound 1 decreasesintestine wall hyperplasia which is an accessory lesion of the erosion,and decreases anemia as a result of melena due to the erosion.

Histopathological study: As a result of histopathological studies, aremarkable decrease of inflammation at the submucosa in the erosionformed region was confirmed in the groups treated with the compound 1.Further, it was confirmed that normal tissue reconstruction byregeneration of the mucosa took place, and the strength and function asthe mucosal tissue tended to be restored.

Test Example 2

Therapeutic Effect on Trinitrobenzene Sulfonic Acid (TNBS) Induced RatCrohn's Disease Model

The therapeutic effect of the compound 1 on TNBS induced rat Crohn'sdisease model was studied by the following method.

(1) SD male rats (12 weeks old) were anesthetized with Nembutal andtheir abdomen was opened up, a TNBS solution (TNBS 160 mg/ml ethanol)was administered in 1 ml/kg in the colon located 10 cm below theileocecum, and their abdomen was closed to prepare models, which weredivided into a non-treated group and a group treated with the compound1, each group consisting of 6 rats. No such a treatment was carried outfor normal group rats. After preparation of the models, a drugformulation of the compound 1 of Test Example 1 diluted with distilledwater was perorally administered to rats of the group treated with thecompound 1 once a day for 7 days in a dosage of 10 mg/kg/day ascalculated as anhydride of the compound 1. After completion ofadministration period, visual change, small intestine weight and mucosalmyeloperoxidase activity in small intestine (mucosal MPO activity) wereobserved or measured. The visual change was evaluated by digitizing andcompiling various changes. The ratio of the small intestine weight tothe body weight was also calculated from the small intestine weight andthe body weight. The results are shown in Table 2.

TABLE 2 Examination results Small Ratio of small Mucosal intestineintestine to Visual MPO weight body weight score activity Group n MeanSD Mean SD Mean SD Mean SD Normal 6 1.11 0.12 0.0030 0.0003 1.5 0.8 0.480.22 group Non-treated 6 2.18 0.45 0.0065 0.0009 7.8 0.8 8.93 3.71 group## ### ## ## Treated 5 1.63 0.21 0.0042 0.0005 4.2 0.4 0.89 0.05 group **** ** ** Statistical Evaluation Comparison between normal group andnon-treated group #, ##, ###: p < 0.05, p < 0.01, p < 0.001 Comparisonbetween non-treated group and treated group *, **, ***: p < 0.05, p<.0.01, p < 0.001

In the non-treated group, increase in values of the small intestineweight, the ratio of the small intestine to the body weight, the visualscore and the mucosal MPO activity was confirmed, and an inflammatoryreaction and tissue impairment in the small intestine were confirmed. Itwas shown that in the group treated with the compound 1, increase insuch examination values was suppressed, and the inflammatory reactionand tissue impairment in the small intestine were decreased.

What is claimed is:
 1. A method for preventing or treating a digestivesystem disease, comprising administering to a subject in need thereof aneffective amount of a diaminotrifluoromethylpyridine compound or itssalt, wherein said compound is represented by formula (I):

wherein X is a —CW R¹ group, a —COCOR² group, a —CW¹ NHCOR² group, a—C(═W¹)W²R³ group or a —CW¹N(R⁴)R⁵ group; Y is an alkyl group, a —CW³R⁶group, a —COCOR⁷ group, a —NHCOR⁷ group, a —C(═W³)W⁴R⁸ group, a(NH)_(m)SO₂R⁹ group, a —(NH)_(m)SO₂OR¹⁰ group or a —(NH)_(m)SO₂N(R¹¹)R¹²group; wherein each of R¹ R⁶ and R⁹, which are independent of oneanother, is a chain hydrocarbon group which may be substituted, amonocyclic hydrocarbon group which may be substituted, a polycyclichydrocarbon group which may be substituted, a monocyclic heterocyclegroup which may be substituted or a polycyclic heterocycle group whichmay be substituted; wherein each of R² and R⁷, which are independent ofeach other, is an alkyl group which may be substituted, an alkoxy groupwhich may be substituted, a phenyl group which may be substituted or aphenoxy group which may be substituted; wherein each of R², R⁸ and R¹⁰,which are independent of one another, is an alkyl group which may besubstituted, an alkenyl group which may be substituted, an alkynyl groupwhich may be substituted, a cycloalkyl group which may be substituted, aphenyl group which may be substituted or a benzyl group which may besubstituted; wherein each of R⁴, R⁵, R¹¹ and R¹², which are independentof one another, is an alkyl group which may be substituted; each of W¹,W², W³ and W⁴ which are independent of one another, is an oxygen atom ora sulfur atom; and wherein m is 0 or 1; wherein said compound of formula(I) is not a compound where one of X and Y is a COCF₂X¹ group (whereinX¹ is a hydrogen atom, a halogen atom, an alkyl group or a haloalkylgroup), and the other is a —COCF₂X² group (wherein X² is a hydrogenatom, a halogen atom, an alkyl group, a haloalkyl group or analkylcarbonyl group), a —COOX³ group (wherein X³ is an alkyl group whichmay be substituted or a phenyl group which may be substituted) or a—COX⁴ group (wherein X⁴ an alkyl group, a haloalkyl group, an alkenylgroup, an alkynyl group, a phenyl group which may be substituted, afuranyl group or a naphthyl group).
 2. The method of claim 1, wherein Xis a —CW¹R¹ group or a —C(═W¹)W²R³ group and Y is a —SO₂R⁹ group.
 3. Themethod of claim 1 wherein X is a —CW¹R₁ group or a —C(═W¹)W²R³ group, R¹is an alkyl group which may be substituted, an alkenyl group which maybe substituted, a cycloalkyl group which may be substituted, acycloalkenyl group which may be substituted, a phenyl group which may besubstituted, a tetrahydronaphthyl group which may be substituted, anindanyl group which may be substituted, a furanyl group which may besubstituted or a thienyl group which may be substituted, R³ is an alkylgroup which may be substituted, Y is a —SO₂R⁹ group, and R⁹ is an alkylgroup which may be substituted, an alkenyl group which may besubstituted, a cycloalkyl group which may be substituted, a cycloalkenylgroup which may be substituted or a phenyl group which may besubstituted.
 4. The method of claim 1, wherein X is a —CW¹R¹ group or a—C(═W¹)W²R³ group, R¹ is an alkyl group, a haloalkyl group, analkoxycarbonyl alkyl group, an alkenyl group, a haloalkenyl group, analkenyl group substituted with a thienyl group, a cycloalkyl group, acycloalkyl group substituted with a halogen atom, a phenyl group, aphenyl group substituted with a halogen atom, a phenyl group substitutedwith an alkyl group or a haloalkyl group, a phenyl group substitutedwith an alkoxy group or a haloalkoxy group, a tetrahydronaphthyl group,an indanyl group, a furanyl group or a thienyl group, R³ is an alkylgroup or a haloalkyl group, Y is a —SO₂R⁹ group, and R⁹ is an alkylgroup, a haloalkyl group, a phenyl group, a phenyl group substitutedwith a halogen atom, a phenyl group substituted with an alkyl group or ahaloalkyl group, or a phenyl group substituted with an alkoxy group or ahaloalkoxy group.
 5. The method of claim 1, wherein X is analkoxycarbonyl alkylcarbonyl group, an alkenylcarbonyl group, analkenylcarbonyl group substituted with a thienyl group, acycloalkylcarbonyl group, an indanylcarbonyl group, a furancarbonylgroup, a thiophenecarbonyl group, a tetrahydronaphthylcarbonyl group ora benzoyl group which may be substituted with a halogen atom or a haloalkyl group, and Y is an alkylsulfonyl group.
 6. The method of claim 1,wherein X is a cycloalkylcarbonyl group, a furancarbonyl group or abenzoyl group which may be substituted with halogen, and Y is analkylsulfonyl group.
 7. The method of claim 1, wherein thediaminotrifluoromethylpyridine compound isN-(2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl)cyclohexanecarboxamide,N-(2-methylsulfonylamino-5-trifluoromethy-3-pyridyl)-4-fluorobenzamide,N-(2-isopropylsulfonylamino-5-trifluoromethyl-3-pyridyl)-3-fluorobenzamide,N-(2-methylsulfonylamino-5-trifluoromethyl-3-pyridyl)-2-furancarboxamideorN-(2-isopropylsulfonylamino-5-trifluoromethyl-3-pyridyl)cyclopentanecarboxamide.8. The method of claim 1 wherein the diaminotrifluoromethylpyridinecompound isN-(2-ethylsulfonylamino-5-trifluoromethyl-3-pyridyl)cyclohexanecarboxamide.
 9. The method of claim 1 that is a method for preventing adigestive system disease.
 10. The method of claim 1 that is a method fortreating a digestive system disease.
 11. The method of claim 1 thatcomprises treating a disease selected from the group consisting ofulcerative colitis (nonspecific idiopathic colitis), Crohn's disease(regional enteritis), large intestine Crohn's disease (granulomatouscolitis or regional colitis), entero-Behcet's disease, infectiousenteritis, ischemic enteritis, radioenteritis, drug enteritis, irritablebowel syndrome, digestive ulcer, gastric ulcer, duodenal ulcer, andgastritis.
 12. The method of claim 1 comprising treating a subject withulcerative colitis.
 13. The method of claim 1 comprising treating asubject with Crohn's Disease.
 14. The method of claim 1 furthercomprising administering at least one other drug, therapeutic agent orherbal remedy.
 15. The method of claim 1 comprising administering analkaline metal salt, an alkaline earth metal salt or an organic aminesalt of said compound.
 16. The method of claim 1 comprisingadministering said compound perorally.
 17. The method of claim 16,wherein said compound is formulated in a manner to prolong its retentiontime in the digestive canal.
 18. The method of claim 1 comprisingadministering said compound in the form of a tablet, capsule, powder,granule, troche, liquid, suspension, emulsion, ointment, suppository orsyrup.
 19. The method of claim 1 comprising administering said compoundparenterally.
 20. The method of claim 1 comprising administering saidcompound topically or by rectal administration.
 21. The method of claim1 comprising administering said compound via the respiratory airway orby inhalation.
 22. The method of claim 1 comprising administering to adaily dose ranging from 0.1 mg to about 10 g of saiddiaminotrifluoromethylpyridine compound or its salt.
 23. The method ofclaim 1 comprising administering a daily dose ranging from 1 mg to about1 g of said diaminotrifluoromethylpyridine compound or its salt.
 24. Amethod for decreasing intestinal wall erosion and/or hyperplasia in thelarge intestine comprising administering the compound of claim
 1. 25. Amethod for inducing regeneration of the intestinal mucosa comprisingadministering the compound of claim
 1. 26. A method for decreasing aninflammatory reaction or tissue impairment in the small intestinecomprising administering the compound of claim 1.